Project 6, entitled Network biomarkers will develop novel network connectivity analyses for detecting and monitoring preclinical FTD and early clinical bvFTD. The overarching goal is to move beyond prevaling barriers to implementing intrinsic connectivity network (ICN) mapping as a neurodegenerative disease biomarker. Recent research suggests that each neurodegenerative syndrome targets a specific, large-scale distributed network that can be identified in the healthy brain using ICN methods. As a non-invasive, repeatable, dynamic functional imaging modality, ICN mapping has the potential to play a vital role in FTD drug discovery. How ICNs break down in presymptomatic FTD gene mutation carriers and patients with early bvFTD, however, remains unknown. Furthermore, no data are available regarding longitudinal ICN changes in FTD or how ICN integrity relates to clinical deficits. Existing barriers to addressing these questions and developing ICN biomarkers include lack of reliability data in patients and the need to build methodological consensus. In Project 6, we will seek to overcome these issues and address key questions about early sites, longitudinal progression, and symptom-relevance of ICN changes by studying subjects with preclinical FTD (asymptomatic FTD gene mutation carriers), early clinical bvFTD, early svPPA, and healthy controls recruited through Core A (Clinical), genotyped through Core D (Genetics), imaged through Core E (Imaging) and characterized in terms of emotion processing in Project 3 (Emotions). We will pursue the following specific aims: (1) To determine the most reliable and sensitive ICN analysis strategy for detecting preclinical FTD and early clinical bvFTD at first evaluation, (2) To identify longitudinal network connectivity changes in preclinical FTD and early clinical bvFTD over 6- and 12-month intervals, and (3) To link specific ICN changes to loss of emotional functioning in preclinical FTD, early bvFTD and svPPA (with Project 3). Successful completion of the proposed studies could help provide the field with a non-invasive diagnostic and disease monitoring neuroimaging biomarker for early FTD and, potentially, for related neurodegenerative diseases.